An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth

Rubén A Bartolomé,Alberto Peláez-García,Inmaculada Gomez,Sofía Torres,María Jesús Fernandez-Aceñero,Beatriz Escudero-Paniagua,J Ignacio Imbaud,J Ignacio Casal

doi:10.1074/jbc.m114.600502

Rubén A Bartolomé, Alberto Peláez-García + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m114.600502

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Abstract

Little is known about the mechanism of integrin activation by cadherin 17 (CDH17). Here we observed the presence of a tri-peptide motif, RGD, in domain 6 of the human CDH17 sequence and other cadherins such as cadherin 5 and cadherin 6. The use of CDH17 RAD mutants demonstrated a considerable decrease of proliferation and adhesion in RKO and KM12SM colon cancer cells. Furthermore, RGD peptides inhibited the adhesion of both cell lines to recombinant CDH17 domain 6. The RGD motif added exogenously to the cells provoked a change in β1 integrin to an active, high-affinity conformation and an increase in focal adhesion kinase and ERK1/2 activation. In vivo experiments with Swiss nude mice demonstrated that cancer cells expressing the CDH17 RAD mutant showed a considerable delay in tumor growth and liver homing. CDH17 RGD effects were also active in pancreatic cancer cells. Our results suggest that α2β1 integrin interacts with two different ligands, collagen IV and CDH17, using two different binding sites. In summary, the RGD binding motif constitutes a switch for integrin pathway activation and shows a novel capacity of CDH17 as an integrin ligand. This motif could be targeted to avoid metastatic dissemination in tumors overexpressing CDH17 and other RGD-containing cadherins.

Highlights

The interaction between cadherin 17 and ␣2␤1 integrin promotes cell adhesion and proliferation
We found that the human 7D-cadherin, cadherin 17 (CDH17), contains an RGD site with the capacity to act as a new ligand for integrin binding
Interaction of CDH17 with ␣2␤1 integrin required the presence of the RGD binding site; the capacity of the RGD motif to bind ␣2␤1 integrin in colon cancer cells was supported by different binding and cell adhesion assays, including siRNA experiments; the CDH17-RGD ectodomain was able to bind colon cancer cells and activate ␤1 integrin when added exogenously; and, after in vivo inoculation, tumor cells expressing mutant CDH17 RAD showed a considerable delay in tumor growth and liver colonization

Summary

Background

The interaction between cadherin 17 and ␣2␤1 integrin promotes cell adhesion and proliferation. Results: Cadherin 17 contains an RGD motif that constitutes the critical switch for integrin binding and activation. In vivo experiments with Swiss nude mice demonstrated that cancer cells expressing the CDH17 RAD mutant showed a considerable delay in tumor growth and liver homing. The RGD binding motif constitutes a switch for integrin pathway activation and shows a novel capacity of CDH17 as an integrin ligand. This motif could be targeted to avoid metastatic dissemination in tumors overexpressing CDH17 and other RGD-containing cadherins. This report describes, for the first time, the capacity of CDH17 to act as an integrin ligand through an RGD motif to promote integrin activation that results in enhanced tumor proliferation

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DISCUSSION